tolvaptan (Rx)

Brand and Other Names:Samsca, Jynarque
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet (Samsca)

  • 15mg
  • 30mg

tablet (Jynarque)

  • 15mg
  • 30mg
  • 45mg
  • 60mg
  • 90mg

Hyponatremia

Samsca only

Indicated for adults with clinically significant euvolemic or hypervolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and SIADH

Initial: 15 mg PO qDay

Maintenance: May increase to 30 mg qDay after at least 24 hr to achieve the optimal serum sodium level; not to exceed 60 mg/day

Not to exceed 30 days of treatment

Polycystic Kidney Disease

Jynarque only

Indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD)

Initial: 45 mg PO taken on waking and 15 mg taken 8 hr later (ie, 60 mg/day)

Titrate to 60 mg plus 30 mg, then to 90 mg plus 30 mg per day if tolerated, with at least weekly intervals between titrations

Patients may down-titrate based on tolerability

Encourage patients to drink enough water to avoid thirst or dehydration

Dosage Modifications

Renal impairment

  • CrCl 10-79 mL/min: No dosage adjustment required
  • CrCl <10 mL or dialysis: Not recommended; drug effects on serum sodium levels are likely lost at very low levels of renal function
  • Anuria: Contraindicated; no benefit expected

Hepatic impairment

  • Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent
  • Underlying liver disease: Avoid use

Strong CYP3A inhibitors

  • Coadministration with strong CYP3A inhibitors: Contraindicated; causes a marked (5-fold) increase in tolvaptan exposure

Moderate CYP3A inhibitors (Samsca)

  • Not studied; prescribing information recommends avoiding coadministration

Moderate CYP3A inhibitors (Jynarque)

  • Reduce the dose if coadministered with moderate CYP3A inhibitor; consider further reductions if patients cannot tolerate the reduced dose
  • Interrupt temporarily for short-term therapy with moderate CYP3A inhibitors if the recommended reduced doses are not available
  • Dose reduction with moderate CYP3A inhibitors
    • Taking 90 mg and 30 mg: Reduce to 45 mg and 15 mg
    • Taking 60 mg and 30 mg: Reduce to 30 mg and 15 mg
    • Taking 45 mg and 15 mg: Reduce to 15 mg and 15 mg

Potent CYP3A inducers

  • Coadministration with potent CYP3A inducers: Monitor and adjust tolvaptan dose accordingly; potent inducers reduce tolvaptan plasma concentrations by 85%

P-gp inhibitors

  • Coadministration with P-gp inhibitors: Monitor; tolvaptan dose may need to be reduced

Dosing Considerations

Limitations of use (Samsca)

  • Patients should be hospitalized for initiation and reinitiation of therapy to evaluate the therapeutic response and because too-rapid correction of hyponatremia can cause osmotic demyelination
  • Do not use in patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms
  • It has not been established that raising serum sodium with tolvaptan provides a symptomatic benefit to patients
  • Monitor serum sodium

Jynarque

  • Monitoring to mitigate risk of liver injury
    • Perform blood testing for ALT, AST, and bilirubin prior to initiating, at 2 and 4 weeks after initiation, monthly for 18 months, and q3Months thereafter
    • Monitor for concurrent symptoms that may indicate liver injury

Safety and efficacy not established

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Interactions

Interaction Checker

and tolvaptan

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     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Samsca

            • Nausea (21%)
            • Thirst (16%)
            • Dry mouth (13%)
            • Pollakiuria (4-11%)
            • Urinary frequency/output increased (11%)

            Jynarque

            • Increased urination (69.5%)
            • Thirst (63.7%)
            • Dry mouth (16%)
            • Fatigue (13.6%)
            • Diarrhea (13.3%)
            • Dizziness (11.3%)

            1-10%

            Samsca

            • GI bleeding with preexisting cirrhosis (10%)
            • Weakness (9%)
            • Constipation (7%)
            • Hyperglycemia (6%)
            • Anorexia (4%)
            • Pyrexia (4%)

            Jynarque

            • Dyspepsia (7.9%)
            • Decreased appetite (7.2%)
            • Abdominal distension (4.9%)
            • Dry skin (4.9%)
            • Rash (4.2%)
            • Hyperuricemia (3.9%)
            • Palpitations (3.5%)

            Postmarketing Reports

            Neurologic: Osmotic demyelination syndrome

            Investigations: Hypernatremia

            Immune system disorders: Hypersensitivity reactions including anaphylactic shock and rash

            Hepatobiliary disorders: Liver failure requiring transplantation

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            Warnings

            Black Box Warnings

            Samsca

            • Initiate or reinitiate only in a hospital where serum sodium level can be monitored closely
            • Too-rapid correction of hyponatremia (eg, >12 mEq/L/24 hr) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death
            • In susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, slower rates of correction may be advisable
            • Not for use for ADPKD because of risk of hepatoxicity; tolvaptan (Jynarque) is specifically indicated for ADPKD

            Jynarque

            • Can cause serious and potentially fatal liver injury; acute liver failure requiring liver transplantation reported
            • Measure ALT, AST and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, monthly for the first 18 months ,and q3Months thereafter
            • Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity
            • Because of the risks of serious liver injury, available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Jynarque REMS Program; additional information is available at www.jynarquerems.com or by telephone at 1-877-726-7220

            Contraindications

            Concomitant strong CYP3A inhibitors

            Hypersensitivity (eg, anaphylactic shock, generalized rash)

            Anuria

            Unable to sense or respond to thirst

            Hypovolemia

            Samsca

            • Use in patients with ADPKD outside of FDA-approved REMS (see Black Box Warnings)
            • Urgent correction of hypovolemia required

            Jynarque

            • History, signs, or symptoms of significant liver impairment or injury; this contraindication does not apply to uncomplicated polycystic liver disease
            • Uncorrected abnormal blood sodium concentrations
            • Uncorrected urinary outflow obstruction

            Cautions

            Hypernatremia, hypovolemia, and/or dehydration; encourage patient to drink whenever thirsty

            Risk of hyperkalemia

            Osmotic demyelination syndrome is a risk associated with too-rapid correction of hyponatremia (see Black Box Warnings)

            Can cause serious and potentially fatal liver injury; acute liver failure requiring liver transplantation reported; discontinue if laboratory abnormalities or signs or symptoms of liver injury are evident (see Black Box Warnings)

            Drug interaction overview

            • Hypertonic saline: Concomitant use not recommended
            • Diuretics: Increases risk for dehydration
            • P-gp inhibitors: Monitor; dose reduction may be required
            • Drugs that increase serum potassium: Tolvaptan may have additive hyperkalemic effects if coadministered
            • P-gp substrates: Tolvaptan may increase AUC and Cmax of P-gp substrates
            • OATP1B1/3 and OAT3 substrates: Avoid concomitant use; tolvaptan may increase plasma concentrations of these substrates
            • BCRP substrates: Avoid concomitant use; tolvaptan is an inhibitor of BCRP
            • V2-receptor agonists: Avoid concomitant use; tolvaptan, a V2-antagonist, interferes with V2-agonist activity (eg, desmopressin [dDAVP])
            • CYP3A
              • Tolvaptan is a substrate of CYP3A
              • CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations
              • Coadministration with strong CY3A inhibitors: Contraindicated
              • Coadministration with moderate CYP3A inhibitors: Avoid (Samsca); modify dose (Jynarque)
              • Coadministration with CYP3A inducers: Monitor; dosage increase may be required
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            Pregnancy & Lactation

            Pregnancy

            Available data are insufficient to determine if there is a drug-associated risk of adverse developmental outcomes

            Animal studies

            • In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis
            • At maternally nontoxic doses, tolvaptan did not cause any developmental toxicity in rats or in rabbits at exposures approximately 4- and 1-times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 90/30 mg; however, effects on embryo-fetal development occurred in both species at maternally toxic doses

            Lactation

            Data are not available on the presence of tolvaptan in human milk, the effects on the breastfed infant, or the effects on milk production

            Tolvaptan is present in rat milk

            Because of the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities (eg, hypernatremia), hypotension, and volume depletion in breastfed infants, advise women not to breastfeed during treatment

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Selective vasopressin V2-receptor antagonist that causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentration

            Absorption

            Absolute bioavailability: Unknown; at least 40% of the dose is absorbed as tolvaptan or metabolites

            Peak plasma concentration: 2-4 hr

            Distribution

            Protein bound: 99%

            Vd: 3 L/kg

            Metabolism

            Eliminated entirely by nonrenal routes and mainly, if not exclusively, metabolized by CYP3A

            Elimination

            Half-life, terminal: 12 hr

            Clearance: 4 mL/min/kg

            Excretion: Nonrenal

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            Administration

            Oral Administration

            May take with or without food

            Samsca

            • Do not exceed 30 days of administration to minimize risk of liver injury
            • Following discontinuation, advise patient to resume fluid restriction and monitor changes in serum sodium and volume status

            Jynarque

            • If a dose is not taken at the scheduled time, take the next dose at its scheduled time

            Storage

            Tablets (Samsca): Store at 15-30°C (59-86°F)

            Tablets (Jynarque): Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.